The sweet taste receptor protein T1r2+T1r3, encoded by the Tas1r2 and Tas1r3 genes, mediates taste responses to non-caloric sweeteners. However, Tas1r3 knockout mice generated in our group retain taste nerve responses to glucose and maltose. Glucose transporters (GLUTs) and metabolic sensors (KATP) expressed selectively in Tas1r3-positive taste cells may underlie taste responses of Tas1r3 knockout mice to sugars. Tas1r3-positive taste cells also express two intestinal type enzymes, sucrase-isomaltase and maltase-glucoamylase, that hydrolyze sucrose and maltose. The general goals of this grant are to elucidate the mechanisms underlying taste detection of sugars and to identify transcription factors that control the generation of sweet-responsive taste cells. The experiments proposed here use gene knockout mice and enzyme inhibitors to assess the involvement of KATP, sucrase-isomaltase and maltase-glucoamylase in taste responses to sugars. In the first two aims of the proposal we combine transgenic, physiological and behavioral methods to determine: 1. If sugar transporters and KATP metabolic sensors contribute to taste transduction of sugars, and 2. If intestinal disaccharidase enzymes expressed in Tas1r3-positive taste cells contribute to taste transduction of sugars. In the third aim we build on results from bioinformatic analysis of genes expressed in taste cells to: (a) Identify transcription factors selectively expressed in Tas1r3+ taste cells, and (b) Determine if loss of transcription factors selectively expressed in Tas1r3-positive taste cells affects generation and function of these cells. Ultimately, these studies may provide insights into why sugars are preferred over non-caloric sweeteners, lead to the generation of superior non-caloric sweeteners, and provide a means to regulate sweet-responsive taste cells so as to decrease the drive for consuming sugar. This multidisciplinary approach has promise for providing significant new insights into the function and regulation of sweet taste receptor cells. This proposal has medical relevance to gustatory function, appetite, satiety, diabetes and obesity.